Abstract Sepsis represents a huge unmet medical need: it annually afflicts nearly 1 million individuals in the United States, killing >200,000. The pathophysiology of sepsis and other inflammatory disorders is mediated by dysregulated innate immune responses and abnormally elevated cytokine levels. The inflammatory reflex consists of a neural-immune circuit composed of sensory (afferent) and motor (efferent) vagal neurons that regulate cytokine production in the spleen. The molecular mechanisms of the motor arc are well defined, but considerably less is known about the sensory arc of the inflammatory reflex. In the motor arc, action potentials arise in the vagus nerve, travel in the splenic nerve, and culminate on lymphocytes that are activated to produce acetylcholine, a neurotransmitter molecule that inhibits cytokine production via signaling through ?7 nicotinic acetylcholine receptor (?7nAChR), expressed on macrophages and monocytes. Using novel electrophysiological recording and decoding methods, we recently identified cytokine-specific sensory neural signals in the vagus nerve. These studies revealed a novel role for an ion channel, transient receptor potential ankyrin-repeat 1 (TRPA1), in the afferent vagus nerve response to IL-1?, and selective activation of TRPA1 afferent fibers in the vagus nerve, which also suppresses TNF levels in endotoxemia. Here, we hypothesize that TRPA1 plays an essential role in mediating interleukin-1? (IL-1?)-induced vagus nerve activation, and selective stimulation of TRPA1 expressing vagus nerve fibers will improve survival and pathophysiology in sepsis. This hypothesis will be addressed in the following two Specific Aims: Specific Aim 1. Elucidate the role of TRPA1 in mediating IL-1?-induced activation of the inflammatory reflex. Specific Aim 2. Assess the dynamics of vagus nerve activity and evaluate the effects of selective TRPA1 stimulation on survival and pathophysiology in sepsis. We propose to utilize a novel approach that integrates experiments assessing direct binding and colocalization of TRPA1 with IL-1Rs on the sensory neurons, analysis of action potential generation in neurons, and evaluating the role of TRPA1-dependent pathophysiological effects in animals subjected to sepsis. This significant new research will provide novel and impactful data for an innovative molecular mechanism of the afferent (sensory) arc of the inflammatory reflex and its role in sepsis. This data will pave the way to develop novel therapeutic modalities for the prevention and treatment of sepsis/septic shock.